Immunosuppression in animals can result from a depressed capacity to produce species of lymphokines which are essential to the development of protective forms of immunity. Imbalances between various types of lymphokines, where species of lymphokines capable of promoting one form of immune response exhibit enhanced production, while those lymphokines needed to promote protective forms of immunity are suppressed, can also lead to immunosuppression. Individuals may be immunosuppressed as a consequence of endogenous elevations in adrenal glucocorticosteroid (GCS) levels. This condition could result from viral infections, from certain bacterial infections, certain parasitic infections, cancer, some autoimmune syndromes, and stress and trauma, or as a secondary consequence to any clinical condition that causes an elevated production of interleukin-1 (IL-1). Plasma glucocorticoid steroid levels also can be elevated exogenously as a consequence of therapeutic treatment for a variety of clinical conditions. In addition to the above, it is also well known that certain essential functions of the immune system decline with age, a situation which correlates with elevations in adrenal output of glucocorticoid steroids and depressions in production of other types of adrenal steroid hormones.
It is known that lymphocytes exported from the thymus undergo a series of differentiation events which confer upon them the capacity to recognize and respond to specific peptide antigens presented appropriately in the context of self major histocompatibility complex (MHC) molecules. Mechanistically, thymic maturation is a complex process which includes an irreversible rearrangement of T cell receptor genes, the cell surface expression of these gene products as disulfide-linked heterodimers, positive and negative selection processes to provide appropriate restriction and avoidance of self-reactivity, and the synthesis and expression of CD4 or CD8 as accessory adhesion molecules. Microenvironmental influences within the thymus play an essential role in the fidelity of this process.
Subsequent to leaving the thymic microenvironment, mature T lymphocytes gain access to the recirculating T cell pool where they move freely via the blood between mucosal and nonmucosal lymphoid compartments in the mammalian host (Hamann et al. (1989), Immunol. Rev. 108:19). T-lymphocyte expression of lymphoid tissue-specific homing receptors, which are complementary for vascular addressins on high endothelial venules present in Peyer's patches and peripheral lymph nodes, provide a biochemical means for selectivity to this recirculation process (id.). Non-activated lymphocytes can move freely between mucosal and nonmucosal lymphoid tissues due to the presence of both types of homing receptors on their plasma membranes (Pals et al. (1989), Immunol. Rev. 108:111). Effector lymphocytes, and antigen-activated immunoblasts which are stimulated in a particular site in the body, however, exhibit a far more selective migratory behavior. These cells move primarily to tissues originally involved in antigen exposure and cellular activation (Hamann et al. (1989), supra; Pals et al. (1989), supra.).
An immune response is initiated following T cell recognition of antigen peptides in the context of self MHC molecules and generally takes place in one of the host's secondary lymphoid compartments. Cellular activation is triggered by the binding of antigen to the T cell receptor (TCR), forming an antigen/TCR complex which transduces the antigen-specific extracellular stimulation across the plasma membrane, and generates intracellular signals which include the activation of protein kinase C and the increases in intracellular calcium. While signal transduction can lead to T cell unresponsiveness, positive signal transduction events trigger a series of additional biochemical processes. One consequence of this activation is the stimulated production of a number of biologically active molecules which are collectively termed lymphokines. (See, Alcover et al. (1987), Immunol. Rev. 95:5; Gelfand et al (1987), Immunol. Rev. 95:59).
The lymphokines, many of which function primarily through autocrine and paracrine mechanisms, serve to mediate numerous effector functions controlled by T cells through their capacity to regulate cellular proliferation, differentiation, and maturation events in lymphocytes, plus other hematopoietic and somatic tissue cells (Paul (1989), Cell 57:521).
Each of the various types of lymphokines exhibit pleiotropic activities, dependent upon the specific type of cellular targets being stimulated. The biological evaluation of recombinant forms of specific lymphokines has determined that individual species can possess both distinct and overlapping cellular activities (Paul (1989), supra). Interleukin-2 (IL-2) and interleukin-4 (IL-4), for example, share the capacity to facilitate T cell growth but are disparate in their relative contribution to cellular and humoral immune responses. Cloned T cell lines, restricted in their capacity to produce individual species of lymphokines, have been described which demonstrate unique capabilities in serving as effector cells or helper cells for various immune responses (Paul (1989), supra; Hayakawa et al. (1988), J. Exp. Med. 168:1825; Mossman et al. (1989), Ann. Rev. Immunol. 7:145).
Treatment of individuals for immunosuppression has been focused on the use of purified lymphokines, usually IL-2, to restore normal propagation of T cells. Illustrative of this are the disclosures of U.S. Pat. No. 4,661,447 (issued Apr. 28, 1987 to Fabricus et al.), U.S. Pat. No. 4,780,313 (issued Oct. 25, 1988 to Koichiro et al.), and U.S. Pat. No. 4,789,658 (issued Dec. 6, 1988 to Yoshimoto et al.). However, the systemic administration of IL-2 for therapeutic purposes has numerous side effects. These side effects include fever, hypotension, hepatic and renal failure, myocardial infarctions, capillary leak syndrome, and massive edema (Dinatello et al. (1987), New England J. Med. 317:940.
Applicants' invention embodies methods for treating immunosuppression which are without the side-effects found with the purified lymphokines. These methods utilize the androgen steroid hormones, more specifically dehydroepiandrosterone (DHEA), the sulfated derivative thereof (DHEA-S), and analogs thereof.
DHEA is steroid hormone that has been extensively studied for many years. It has been reported to be involved in a wide variety of physiologic, immunologic, and pathologic conditions (for reviews, see Regelson et al, (1988), Ann. N.Y. Acad. Sci. 521:260; Gordon et al. (1986), Adv. Enzyme Reg. 26:355-382). Most endocrinologists believe that the primary function of DHEA is to serve as a precursor for the synthesis of testosterone and the estrogens by the gonads. The biosynthetic relationship of DHEA to other steroid hormones is shown in FIG. 1 (taken from Cook and Beastall in Steroid Hormones, A Practical Approach (Green and Leake, eds., IRL Press Limited, 1987). Prior to its release into the bloodstream, the vast majority of newly synthesized DHEA becomes sulfated. The conjugated steroid DHEA-S (shown in FIG. 2), is a secretory product of the adrenal gland in man and certain primates. DHEA-S represents the major steroid hormone in the circulation of humans, and is converted to DHEA via a sulfatase.
Therapeutic uses for DHEA and certain analogs have been reported for diabetes, dry skin, ocular hypertension, obesity, and retroviral infections. Illustrative of these reports are the disclosures of U.S. Pat. No. 4,395,408 (issued Jul. 26, 1983 to Torelli et al.), U.S. Pat. No. 4,518,595 (issued May 21, 1985 to Coleman et al.), U.S. Pat. No. 4,542,129 (issued Sep. 17, 1985 to Orentreich), U.S. Pat. No. 4,617,299 (issued Oct. 14, 1986 to Knepper), U.S. Pat. No. 4,628,052 (issued Dec. 9, 1986 to Peat), U.S. Pat. No. 4,666,898 (issued May 19, 1987 to Coleman et al.), European Patent Application No. 0 133 995 A2 dated Feb. 8, 1984 (inventor, Schwartz et al.), and UK Patent Application No. GB 2 204 237 A dated Apr. 14, 1988 (inventor, Prendergast).